Inflammatory or degenerative diseases, including diseases of the joints, e.g. osteoarthritis (OA), rheumatoid arthritis (RA) or juvenile rheumatoid arthritis (JRA), and including inflammation that results from autoimmune response, e.g. lupus, ankylosing spondylitis (AS) or multiple sclerosis (MS), can lead to substantial loss of mobility due to pain and joint destruction. Cartilage that covers and cushions bone within joints may become degraded over time thus undesirably permitting direct contact of two bones that can limit motion of one bone relative to the other and/or cause damage to one by the other during motion of the joint. Subchondral bone just beneath the cartilage may also degrade. However, compounds helpful in preventing bone loss will not necessarily prevent cartilage degradation. Cartilage may be degraded by proteases present in synovial fluid that covers the cartilage surface or from white blood cells that infiltrate the joint space.
Diseases such as osteoarthritis are multimodal in nature, rendering it difficult for any single therapeutic agent to effectively treat all of the symptoms of the disease. Inflammatory or degenerative diseases of the joints have been treated with a variety of therapeutic agents, including a range of non-steroidal anti-inflammatory drugs (NSAIDs) that possess both analgesic and anti-inflammatory properties, but without ideal clinical success in many instances. The NSAIDs in particular provide symptomatic relief but fail to adequately protect the joints from further disease progression. Monotherapy to date has failed to adequately provide both a chondroprotective effect while also providing improved mobility and reduced pain, all of which are attributes for disease-modifying osteoarthritis drugs (DMOADs). Additionally, some therapeutic agents have shown undesirable side effects at the dosages required for therapeutic efficacy.